Retroviruses enter cells through specific cell-surface receptors and then embark on a journey that ultimately leads to the establishment of the integrated proviral DNA. The steps of the journey include the reverse transcription of the viral RNA into DNA, the trafficking of the viral protein-DNA complex through the cytoplasm, the entry of the complex into the nucleus, and the insertion of the linear viral DNA into the host genome. All these steps are likely to involve specific interactions of viral proteins with host machinery. Our knowledge of the details of these interactions is very limited but is rapidly expanding, and should provide a deeper understanding of the pathways and components used by the different classes of retroviruses. This knowledge in turn should enable the development of better and more efficient retroviral vectors for use in gene therapy protocols in vivo.